PROJECT SUMMARY Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease of unknown etiology. Current estimates of disease incidence are 93.7 per 100,000 and include over 125,000 cases in the United States. Recently the FDA approved two drugs, pirfenidone and nintedanib. However, these therapies only slow the disease progression but are unable to reverse established fibrosis and cure IPF. Thus, there is an opportunity to develop a combination therapy that enhances the efficacy of the current antifibrotic drugs to treat IPF. According to our new study, proton pump inhibitors (PPIs) might be a choice of drug to combine with pirfenidone for IPF. This conviction stems from our extended studies of high throughput screening (HTS) 130,000 compounds to discover and validate PPIs as significant regulators of processes involved in lung inflammation and fibrosis using molecular, cell biological and preclinical models. In addition, bioinformatics analysis of our interstitial lung disease (ILD) database of 130 IPF patients indicated that patients who happen to be on PPIs had significant lung transplant-free survival compared to controls (1241 days Vs 730 days, p<0.005). Recently, the evidence-based guideline for treatment of IPF conditionally recommended the use of PPIs in IPF. More recently, data from 623 IPF patients who participated in pirfenidone clinical trials indicated that the patients who were on a combined pirfenidone plus PPI therapy had more favorable outcomes including progression-free survival compared to IPF patients who were on pirfenidone alone. However, neither the conditional recommendation of PPIs for IPF nor the promising anecdotal evidence is based on molecular understanding of how PPIs regulate the disease process in IPF and how they interact with the antifibrotic drugs Our mechanistic studies indicate that PPIs independently inhibit inducible nitric oxide synthase (iNOS) while upregulating heme oxygenase (HO1) expression in IPF lung fibroblasts to influence processes involved in lung remodeling. Our preliminary data of combined pirfenidone and esomeprazole therapy demonstrates profound inhibition of fibroblast proliferation and collagen deposition to enhance antifibrotic efficacy. Accordingly, we plan to test our central hypothesis ?suppression of iNOS, and activation of HO1 by esomeprazole, together with the antifibrotic action of pirfenidone, is able to slow or halt established lung fibrosis orchestrated by dysregulated nitrosative/oxidative stress and fibroproliferation?. To test this, we propose the following aims: i) understand the mechanism(s) by which dysregulated iNOS-HO1 promotes fibrogenesis. Here, we plan to evaluate the mechanism by which iNOS suppression and HO1 activation regulates fibroblast proliferation and collagen production ii) decipher interaction(s) between PPI and iNOS/HO1 to influence the disease process in IPF. iii) evaluate the in vivo efficacy of esomeprazole and pirfenidone combination in two models of lung injury. This is an innovative project proposing to combine a promising generic drug with an FDA-approved antifibrotic drug to effectively slow or halt established lung fibrosis.